Combination therapies of chemotherapy and immune checkpoint inhibitors have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare MSI-H cases, despite their success in other solid tumors. Most prior studies have been conducted in advanced disease. Here, we present clinical, pathologic, and translational results from a phase 1b/2 investigator-initiated study evaluating neoadjuvant modified FOLFIRINOX (mFFX) plus nivolumab in patients with borderline-resectable (BR) PDAC. Among 28 patients enrolled, 22 (79%) proceeded to surgery. Treatment was well tolerated with no significant delays or surgical complications, meeting the primary endpoint. Among patients who underwent surgical resection, median disease-free survival was 19.7 months, median progression-free survival was 26 months (95% CI: 14.7-34.3) and median overall survival was 38 months (95% CI: 27.9-not reached). The regimen demonstrated an acceptable safety profile, with all Grade 3-4 treatment-related adverse events due to chemotherapy and no Grade 3 immune related adverse events observed. Treatment effects were assessed using paired pre- and post-treatment samples and by comparing post-treatment tumors from the nivolumab cohort to historical BR mFFX-only controls. In paired analyses, intra-tumoral CD8 T cells and plasma cells increased together; in between-group comparisons, plasma cells were significantly higher in the nivolumab cohort, with a modest CD8 T cell increase. Immunohistochemistry revealed that plasma cell abundance correlated with dense intra-tumoral lymphoid aggregates lacking germinal center-like morphology, a pattern consistent with extrafollicular B cell differentiation. Single-cell spatial transcriptomics identified irregular lymphoid aggregates with high plasma cell to B cell ratios that were enriched for terminally exhausted CD8 T cells and de-enriched for progenitor exhausted CD8 T cells and central memory CD4 T cells. Together, these findings implicate intra-tumoral LA disorganization and skewed T cell subsets as complementary features associated with limited efficacy of PD-1-based chemoimmunotherapy in PDAC. (Clinicaltrials.gov identifier: NCT03970252).
from sddb import Catalog
cohort = Catalog().collection("geo-gse313662")
cohort.members # the 6 datasets as a table
print(cohort.licenses()) # check the terms before you download
sdatas = cohort.to_dict() # {uid: SpatialData}, cached locally
# or keep the .zarr files in a folder of your choice:
# sdatas = cohort.to_dict(dest="data/")Needs pip install lamindb and network access to the Lamin database, which is limited during the alpha. If it fails, use the Client tab.
import lamindb as ln
db = ln.DB("scverse/spatialdata-db")
coll = db.Collection.get(key="geo-gse313662")
coll.ordered_artifacts.to_dataframe() # the 6 members, ordered
# download every member .zarr to the local cache:
paths = [a.cache() for a in coll.ordered_artifacts.all()]# sddb client: download every member .zarr into data/
sddb-cli download --collection geo-gse313662 --dest data/Licenses: 6 NCBI GEO policy
Chemotherapy and immune checkpoint inhibitor combinations have failed to improve survival in pancreatic ductal adenocarcinoma (PDAC), except in rare microsatellite instability-high cases; most studies focused on advanced disease. Here, we present clinical and translational results from a single-arm, prospective phase 1b/2 investigator-initiated study (NCT03970252) evaluating neoadjuvant modified FOLFIRINOX (mFFX) plus nivolumab in patients with borderline-resectable PDAC. The co-primary endpoints of safety and pathological response rate were met, with 22 (79%) of 28 patients proceeding to surgery and no grade ≥3 immune-related adverse events. All grade 3-4 treatment-related adverse events were chemotherapy-related. By CAP scoring, 9% of patients achieved a complete pathologic response, 9% a near-complete response, and 72% a partial response. Secondary endpoints included CA 19-9 response rate, R0 resection rate, objective response rate, and disease-free survival (median 19.7 months, 95% CI: 7.3-30.8). In post-hoc analyses, median progression-free survival was 26 months (95% CI: 14.7-34.3), and median overall survival was 38 months (95% CI: 27.9-not reached). Exploratory gene expression, immunohistochemistry and spatial transcriptomics showed increased intratumoral plasma cells and CD8 T cells in treated patients versus mFFX-only controls, and lymphoid aggregates with high plasma-cell-to-B cell ratios enriched for terminally exhausted CD8 T cells with fewer progenitor exhausted CD8 T cells and central memory CD4 T cells.
@article{Wainberg_2026,
title = {Neoadjuvant modified FOLFIRINOX plus nivolumab in borderline-resectable pancreatic ductal adenocarcinoma: a pilot phase 1 trial},
volume = {17},
ISSN = {2041-1723},
url = {http://dx.doi.org/10.1038/s41467-026-68976-2},
DOI = {10.1038/s41467-026-68976-2},
number = {1},
journal = {Nature Communications},
publisher = {Springer Science and Business Media LLC},
author = {Wainberg, Zev A. and Link, Jason M. and Premji, Alykhan and Zheng, Serena and Srienc, Michael and Hammons, McKensie and Kim, Shineui E. and Li, Luyi and Liu, Zeyu and Tsvetkova, Olga and Abt, Evan R. and Rosen, Lee and Kim, Stephen and King, Jonathan and Hines, O. Joe and Girgis, Mark and Sadeghi, Saeed and Olevsky, Olga and Wong, Deborah and Yonemoto, Lisa and Siney, Ann Marie and Kelly, Kim and Kivork, Christine and Tseng, Chi-Hong and Radu, Caius G. and Dawson, David W. and Donahue, Timothy R.},
year = {2026},
month = Jan
}